Method for treating glaucoma by the topical administration of selectively metabolized beta-blocking agents

ABSTRACT

A method for the treatment of glaucoma or lowering intraocular pressure in a mammal, involving topically administering to the eye of such mammal a selectively metabolized beta-blocking compound of the formula: ##STR1## wherein Ar may be substituted or unsubstituted aromatic, Y may be a straight or branched carbon chain or aralkyl, R may be lower alkyl, lower alkenyl, lower alkynyl, aryl, or aralkyl, and x is an integer from 1 to about 3; or a pharmaceutically acceptable salt thereof. Because of a relatively long duration of action of such compounds in ocular fluids and a relatively short duration of action in the systemic circulation, such compounds are useful for the treatment of excessive intraocular pressure without substantial systemic effects.

This application is a division of application Ser. No. 276,465, filedJune 23, 1981, now U.S. Pat. No. 4,455,317.

BACKGROUND OF THE INVENTION

The present invention relates to a method for the treatment of glaucoma.More particularly, the invention relates to a novel method of treatmentof glaucoma or lowering of intraocular pressure by topicallyadministering beta-adrenergic blocking agents to the eye.

Glaucoma is a condition of the eye characterized by increasedintraocular pressure. Untreated, the condition can eventually lead toirreversible retinal damage and blindness. Conventional therapy forglaucoma has involved topical administration of pilocarpine and/orepinephrine, administered to the eye several times daily.

Various beta-blocking agents may also be used to lower intraocularpressure. Such use is described, for example, in reviews by W. P. Bogerin Drugs, 18, 25-32 (1979) and by T. J. Zimmerman and W. P. Boger inSurvey Ophthmol., 23(6), 347 (1979). The use of beta-blockers for thetreatment of glaucoma is also described in the patent literature. Forexample, U.S. Pat. No. 4,195,085 to Stone discloses a method fortreatment of glaucoma by the ocular administration of a beta-blockingcompound, timolol maleate. U.S. Pat. No. 4,127,674 discloses treatingglaucoma with labetalol, a known antagonist of both alpha and betaadrenergic receptors. However, these methods also possess significantdrawbacks, in that the absorption of the beta-blocking compound into thesystemic circulation can cause undesirable side effects. Such sideeffects result from prolonged beta-blocking action on the heart,bronchioles and blood vessels. For example, according to Physicians'Desk Reference, Charles E. Baker, Jr., 35th Edition, 1981, p. 1233,adverse reactions to the topical use of timolol maleate can includebronchospasm, heart failure, as well as cardiac conduction defects.Accordingly, there is a need for a method of treatment for glaucoma orfor lowering intraocular pressure which is relatively free of unwantedsystemic side-effects.

Certain beta-blocking agents which contain enzymatically labile estergroups are known to exhibit short-acting beta-blocking effects in thesystemic circulation. Such short-acting beta-blocking compounds (SABBs)have been suggested for treatment or prophylaxis of cardiac disorders asa means for reducing heart work or improving rhythmicity for a shortduration. Such short-acting beta-blocking compounds avoid the sometimescounterproductive effects of conventional beta-blocking agents, whoseeffects are long-lived and therefore difficult to precisely control.

SUMMARY OF THE INVENTION

In accordance with the present invention, disclosed herein is a methodfor the treatment of glaucoma or for lowering intraocular pressure in amammal, comprising topically administering to the eye of such mammal abeta-blocking compound of the formula: ##STR2## wherein Y is a straightor branched carbon chain of from 1 to about 10 carbon atoms or aralkylof from 8 to about 20 carbon atoms; R is lower alkyl, lower alkenyl,lower alkynyl, aryl or aralkyl; x is an integer from 1 to about 3; Ar isunsubstituted aromatic or aromatic substituted with lower alkyl, loweralkenyl, lower alkynyl, lower alkoxy, halogen, acetamido, amino, nitro,lower alkylamino, hydroxy, lower hydroxyalkyl, acetyl, cyano, or a groupof the formula ##STR3## wherein A is a direct bond; lower alkylenyl offrom 1 to about 10 carbon atoms; or alkenyl of from 2 to about 10 carbonatoms; or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The above-mentioned short-acting beta-blocking compounds have been foundto effectively reduce intraocular pressure in the eyes of mammals whentopically administered. Because of their short-lived duration of actionin the systemic circulation, toxic side-effects produced by theirmigration out of the eye are consequently reduced. It has further beendiscovered that certain of these compounds show an increased longevityof effect when present in the ocular fluid-compared to the duration oftheir systemic effects. Consequently, the present invention resides inthe treatment of glaucoma or lowering intraocular pressure with abeta-blocking compound which exhibits relatively long duration of actionwhile in the ocular fluid, but which is subject to relatively rapidbreakdown into inactive metabolites upon passage to the systemiccirculation.

In vitro studies in human whole blood indicate that the ester functionsof the compounds used in the method of the invention are subject toenzymatic cleavage. Compounds of the present invention in which thearomatic portion, Ar, is also substituted with an ester-containinggroup, have two or more potentially labile sites for enzymatichydrolysis. The time required for substantially complete disappearanceof the beta-blocking effects of the compounds of the present inventionranges from about 5-10 minutes to about 1 hour or more in the systemiccirculation.

Compounds administered by the method of the present invention arerepresented by the formula: ##STR4## wherein Y may be a straight orbranched carbon chain of from 1 to about 10 carbon atoms, e.g.,methylene, ethylene, propylene, 2-ethylhexylene, 1,1-dimethylethylene,and the like, or aralkyl of from 8 to about 20 carbon atoms, such asdialkylene phenyl, e.g., 4-ethylenebenzyl,1-propylene(4-naphthyl)-2-n-butyl, and the like.

R may be lower alkyl of from 1 to about 10 carbon atoms, such as methyl,propyl, t-butyl, 3-propylheptyl, and the like; lower alkenyl of from 2to about 10 carbon atoms, such as ethenyl, propenyl, 4-ethyl-2-hexenyl,and the like, lower alkynyl of from 3 to about 10 carbon atoms, such aspropynyl, 4-ethyl-3-octynyl, and the like; aryl of from 6 to about 10carbon atoms such as phenyl, 2-tolyl, 2-methoxyphenyl, naphthyl, and thelike or aralkyl, wherein the alkyl portion contains from 1 to about 10carbon atoms and the aryl portion contains from 6 to about 10 carbonatoms, such as benzyl, phenethyl, 1-naphthylpropyl,3,4-dimethoxyphenethyl, and the like.

The amine substituent may contain one or more ester groups, thus x is aninteger from 1 to about 3 provided that when x is greater than 1,different occurrences of the --COOR group may be the same or different.

Ar represents substituted or unsubstituted aromatic, includingmonocyclic, polycyclic, and heterocyclic ring systems. Aromaticsubstituents include lower alkyl, of from 1 to about 10 carbon atoms,lower alkenyl of from 2 to about 10 carbon atoms, lower alkynyl, of from2 to about 10 carbon atoms, lower alkoxy of from 1 to about 10 carbonatoms, halogen, acetamido, amino, nitro, lower alkylamino of from 1 toabout 10 carbon atoms, hydroxy, lower hydroxyalkyl of from 1 to about 10carbon atoms, acetyl, cyano, or a group of the formula ##STR5## whereinA is a direct bond, lower alkylenyl of from 1 to about 10 carbon atoms,or lower alkenyl of from 2 to about 10 carbon atoms. When two or moregroups of the same designation occur in the same formula, those groupsare not necessarily identical. The compounds described herein are notlimited to any particular stereoisomeric configuration.

In preferred compounds Y is a straight or branched carbon chain of from1 to about 6 carbon atoms or aralkyl of from 8 to about 12 carbon atoms.Most preferably, Y is a straight or branched carbon chain of from 1 toabout 4 carbon atoms. R is preferably lower alkyl of from 1 to about 5carbon atoms, lower alkenyl of from 2 to about 5 carbon atoms, loweralkynyl of from 3 to about 5 carbon atoms, aryl of from 6 to about 8carbon atoms, or aralkyl, wherein the alkyl portion contains from 1 toabout 5 carbon atoms and the aryl portion contains from 6 to about 10carbon atoms. Most preferably, R is lower alkyl of from 1 to about 4carbon atoms or aralkyl, wherein the alkyl portion contains from 1 toabout 4 carbon atoms and the aryl portion contains from 6 to about 8carbon atoms. Particularly preferred R groups are methyl and ethyl. Theinteger x is preferably 1 or 2; most preferably 1.

Ar is preferably unsubstituted aromatic or aromatic substituted withlower alkyl of from 1 to about 5 carbon atoms, lower alkenyl of from 2to about 5 carbon atoms, lower alkynyl of from 2 to about 5 carbonatoms, lower alkoxy of from 1 to about 5 carbon atoms, fluoro, chloro,acetamido, amino, nitro, lower alkylamino of from 1 to about 5 carbonatoms, hydroxy, lower hydroxyalkyl of from 1 to about 5 carbon atoms,acetyl, cyano, or a group of the formula ##STR6## wherein A is a directbond, alkylenyl of from 1 to about 5 carbon atoms, such as methylene,ethylene, butylene, and the like, or alkenyl of from 2 to about 5 carbonatoms, such as ethenyl, 2-propenyl, 2-butenyl, and the like, and R islower alkyl of from 1 to about 5 carbon atoms. Most preferably, Ar is2-alkylphenyl, e.g., 2-methylphenyl; 2-alkoxyphenyl, e.g.,2-methoxyphenyl; or 2-alkoxy carbonylphenyl, e.g., 2-methoxycarbonylphenyl.

The compounds of this invention may be administered as theirpharmaceutically acceptable acid addition salts, e.g., as thehydrochloride, sulfate, phosphate, gluconate, tartrate, et cetera.

The beta-blocking compounds used in the present invention along withmethods for their preparation are disclosed in co-pending U.S. patentapplication Ser. No. 211,340, herein incorporated by reference.

The compounds of this invention are advantageously administeredtopically to the eye in the form of a solution, ointment, or solidinsert such as is described in U.S. Pat. No. 4,195,085 to allowcontrolled or delayed release formulations. Formulations may contain theactive compound, preferably, in the form of a soluble acid additionsalt, in amounts ranging from about 0.01 to about 10% by wt.,preferably, from about 0.5% to about 5% by wt. Unit dosages of theactive compound can range from about 0.001 to about 5.0 mg., preferablyfrom about 0.05 to about 2.0 mg. The dosage administered to a patientwill depend upon the patient's needs and the particular compoundsemployed.

Carriers used in the preparations of the present invention arepreferably non-toxic pharmaceutical organic or inorganic compositionssuch as water; mixtures of water and water-miscible solvents, such aslower alcohols; mineral oils; petroleum jellies; ethyl cellulose;polyvinylpyrrolidone and other conventional carriers. In addition, thepharmaceutical preparations may also contain additional components suchas emulsifying, preserving, wetting and sterilizing agents. Theseinclude polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000,1,500, 4,000, 6,000 and 10,000, bacteriocidal components such asquaternary ammonium compounds, phenylmercuric salts known to have coldsterilizing properties and which are non-injurious in use, thimerosal,methyl and propyl paraben, benzyl alcohol, phenyl ethanol, bufferingingredients such as sodium chloride, sodium borate, sodium acetates,gluconate buffers, and other conventional ingredients such as sorbitanmonolaurate, triethanolamine, oleate, polyoxyethylene sorbitanmonopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol,thiosorbitol, ethylenediamine tetracetic acid, and the like.Additionally, suitable ophthalmic vehicles can be used as carrier mediafor the present purpose including conventional phosphate buffer vehiclesystems, isotonic boric acid vehicles, isotonic sodium chloridevehicles, isotonic sodium borate vehicles and the like.

The method of treatment of this invention advantageously involves thetopical administration of eye drops containing the active compound.Formulations for eye drops preferably include the active compound as asoluble acid addition salt in a properly buffered, sterile, aqueousisotonic solution.

The compounds of the present invention are ester group-containingbeta-blockers that have a selective, localized, beta-blocking effect inthe eye after topical administration. Such compounds are thought to berapidly metabolized by plasma and/or liver esterases into inactiveby-products, upon entering the systemic circulation, and are alsothought to be relatively stable in ocular fluids, i.e., lacrimal fluidsand aqueous humor. Consequently, such compounds are useful for thetreatment of glaucoma or for lowering intraocular pressure since theyremain stable when topically applied to the eye but rapidly metabolizewhen subsequently absorbed into the systemic circulation.

Some of the compounds break down in the aqueous humor more rapidly thanothers. Such compounds may advantageously be employed when only atemporary reduction in intraocular pressure is desired, say fordiagnostic procedures. Longer-acting compounds are generally used foreffecting longer-term reductions in intraocular pressure, such as isdesired when treating chronic glaucoma. Thus, the method of the presentinvention provides a very useful thereapeutic alternative for thetreatment of glaucoma or for lowering intraocular pressure.

The present invention is further illustrated by the following exampleswhich are not intended to be limiting.

EXAMPLES I-V

The following compounds were prepared according to the methods disclosedin U.S. patent application Ser. No. 211,340: ##STR7##

EXAMPLE VI

This example describes procedures for the preparation of compound of theformulas: ##STR8##

Ethyl 3-(N-Benzyl-amino)3-methylbutyrate Hydrochloride

A mixture of 14 ml (0.1 mole) of ethyl 3,3-dimethylacrylate and 11 ml(0.1 mole) of benzylamine in 50 ml of USP alcohol previously dried over3Å molecular sieves, was heated to reflux for five days. The reactionmedium was then evaporated under reduced pressure and the resulting oiltaken up in 100 ml of ether. The ethereal solution was refrigerated forfifteen hours, filtered and then washed twice with 100 ml portions ofwater. The ethereal phase was then extracted with 100 ml of 1 N HCl. Theaqueous extract was washed twice with 100 ml portions of ether and thenbasified to pH 8 with solid K₂ CO₃ while under a third 100 ml portion ofether. These phases were separated and the ethereal phase retained andwashed once with 100 ml of water. The ethereal solution was dried overMgSO₄ and evaporated under reduced pressure to provide a mobile clearoil: NMR (CDCl₃) δ1.2 (t, J=7 Hz, 3, --CH₂ CH₃), 1.2 (s, 6, two --CH₃),7.2 (s, 5, Ar). The free amine was converted to its hydrochloride saltby dissolving the oil in 25 ml of reagent alcohol followed by treatmentwith 75 ml ethereal .Hcl. An additional 200 ml of ether was added andthe solution placed in the freezer to effect crystallization. 7.2 gm(31%) of white crystals were obtained: mp 154°-155° C.; NMR (CD₃ OD)δ1.2 (t, J+7 Hz, 3, --CH₂ CH₃), 1.5 (s, 6, two --CH₃), 7.5 (m, 4, Ar).Analysis Calculated for C₁₄ H₂₂ NO₂ Cl: C. 61.86; H, 8.16; N, 5.15.Found: C, 61.96; H, 8.46; N, 5.00.

Ethyl 3-Amino-3-methylbutyrate Hydrochloride

A mixture of 25 g (0.1 mole) of ethyl 3-(N-benzylamino)-3-methylbutyratehydrochloride and approximately 2 g of 10% Pd--C in 250 ml of dried USPalcohol was hydrogenated under 55 psi H₂ for four days. The reactionmedium was then filtered and evaporated under reduced pressure toprovide 18 g (100%) of an amber oil which gradually crystallized uponstanding: mp 82°-83° C.; NMR (CD₃ OD) δ1.2 (t, J=7, Hz, 3, --CH₂ CH₃)1.5 (s, 6, two --CH₃), 2.8 (s, 2, --CH₂ --), 4.2 (q, J=7 Hz, 2, --CH₂CH₃). Analysis Calculated for C₇ H₁₆ NO₂ Cl: C, 46.28; H, 8.88; N, 7.71.Found: C, 46.46; H, 8.98; N, 7.90.

Ethyl 3-[N[2-Hydroxy-3 -(2-methylphenoxy)propyl]amino]-3-methylbutyrateHemioxalate Hemihydrate

A 5 g (0.028 mole) quantity of ethyl 3-amino-3-methylbutyratehydrochloride was dissolved in 25 ml of water. The aqueous solution wasplaced under 50 ml of ethyl acetate and then basified to pH 8 with solidK₂ CO₃. The phases were separated and the aqueous layer extracted twoadditional times with 50 ml portions of ethyl acetate. The combinedorganic phase was dried over 5 g of MgSO₄ and then evaporated underreduced pressure with temperature not exceeding 55° C. The free aminewas obtained as a clear oil: 3.1 g (75%; 0.021 mole); NMR (CD₃ OD) δ1.1(s, 6, two --CH₃), 1.2 (t, J=7 Hz, 3, --CH₂ CH₃), 2.4 (s, 2, --CH₂ --),4.1 (q, J=7 Hz, 2, --CH₂ CH₃). The free amine was then taken up in 25 mlof USP alcohol previously dried over 3Å molecular sieves, and combinedwith 3.4 g (0.021 mole) of 1-(2-methylphenoxy)-2,3-epoxypropane.

The resulting solution was heated to reflux for six hours. The reactionmedium was then evaporated under reduced pressure to an oil which wastaken up in 25 ml portions of water. The ethereal phase was thenextracted with 25 ml portions of water. The ethereal phase was thenextracted with 25 ml of 1 N HCl. The aqueous acid solution was washedwith two 25 ml portions of ether and then basified to pH 8 with solid K₂CO₃ while under a third 50 ml portion of ether. The ethereal phase wasseparated, washed with 25 ml of water, dried over MgSO₄ and evaporatedunder reduced pressure. 2.2 g (0.007 mole) of this free amine was thusobtained as a faintly yellow oil. The oil was taken up in 10 ml ofacetone and added dropwise to a solution of 0.9 g (0.007 mole) of oxalicacid dihydrate in 15 ml acetone. This solution was placed in a freezerto effect crystallization. An initial, small crop of crystals wasobtained which did not agree within ±0.4% of the theoretical elementalanalysis. A second, larger crop, 1 g (14%) was then obtained from themother liquor after returning to the freezer: mp 127°-128° C.; NMR (CD₃OD) δ1.3 (t, J=7 Hz, 3, --CH₂ CH₃), 1.5 (s, 6, two --CH₃), 2.2 (s, 3, Ar--CH₃), 7 (m, 4, Ar). Analysis Calculated for C₁₈ H₂₈ NO₆. 1/2 H₂ O: C,59.48; H, 8.04; N, 3.86. Found: C, 59.56; H, 8.03; N, 3.60.Beta-Blocking Activity in vitro: PA₂ =8.6 (atria).

EXAMPLE VII

This example describes the synthesis of a compound of the formula:##STR9##

Ethyl3-[N-[2-Hydroxy-3-[2-(methoxycarbonyl)phenoxy]propyl]amino]-3-methylbutyrateOxalate

A mixture of 4 g (0.028 mole) of ethyl 3-amino-3-methylbutyrate freeamine and 3.8 g (0.018 mole) of ethyl 2-(2,3-epoxypropoxy)benzoate in 50ml of isopropylalcohol was heated to reflux for six hours. The reactionmedium was then evaporated under reduced pressure to provide an oilwhich was taken up in 50 ml of ether. The ethereal solution was washedfive times with 50 ml portions of water, dried over MgSO₄ and thenevaporated under reduced pressure. 2.4 g (0.007 mole) of a faint yellowoil was obtained and taken up in 15 ml of acetone. The acetone solutionwas added dropwise to 0.9 g (0.007 mole) of oxalic acid dihydrate in 25ml of acetone. This solution was treated with 50 ml of ether andcrystallization occurred after refrigeration to provide 1.8 g (23%) ofwhite crystalline clusters: mp 96°-98° C.; NMR (CD₃ OD) δ1.1 (t, J= 7Hz, 3, --CH₂ CH₃), 1.5 (s, 6, two --CH₃) 3.8 (s, 3, --CO₂ CH₃), 7.4 (m,4, Ar); Analysis Calculated for C₂₀ H₂₉ NO₁₀ : C, 54.17; H, 6.59; N,3.16. Found: C, 54.33; H, 6.87; N, 2.91. Beta-blocking Activity invitro: PA₂ =7.8 (atria). In vivo Duration of action: 5 min. (180 mininfusion) (80% recovery time). Potency: 5.0 mg/kg/180 min.

EXAMPLE VIII

The intraocular pressure lowering effect of the compounds described inExamples I-VII are demonstrated in rabbits with normotensive eyes.

Sterile, isotonic saline solutions of each of the compounds used inprocedures of Examples I to VII are prepared by dissolving 10, 30 and100 mg samples of each of the active compounds in 1 ml of saline to give1%, 3%, and 10% solutions with pH about 6.0-7.0. Free amines require oneequivalent of HCl to effect dissolution.

The intraocular pressure lowering effect of each compound is determinedby treating the eyes of healthy rabbits with the above solutions. Threerabbits are used to evaluate the effect of each drug concentration. Astandard dose of 50 ul of each drug solution is applied to one eye ofeach of the three rabbits. Intraocular pressure of both eyes is measuredwith a pressure tonograph of a Mackay-Marg Tonometer before drugadministration and at 15, 30, 45, 60, 120, 180, 240, 300, 360, 420 and480 min. after dosing. Control rabbits are treated similarly withsterile isotonic saline solution. Intraocular pressure lowering in thetreated eyes is compared with the untreated eyes, with saline treatedeyes and with predrug pressures. Each of the compounds tested exhibitsintraocular pressure-lowering activity.

EXAMPLE IX

The experiment of Example VIII is repeated in all essential details,except that rabbits which have cortuosteroid-induced ocularhypertension, as described by Bonomi, L., et al. Glaucoma, Eds. R.Pittscrick, A. D. S. Caldwell, Academic Press, New York, pp. 99-107(1980), are substituted for the normotensive rabbits. Each of the testcompounds exhibits intraocular pressure-lowering activity in this model.

I claim:
 1. A method for treating glaucoma or for lowering intraocularpressure in a mammal, which comprises topically applying to the eye ofsuch mammal an intraocular pressure-lowering effective amount of acompound represented by the formula: ##STR10## wherein Y is a straightor branched carbon chain of from 1 to about 10 carbon atoms or aralkylof from 8 to about 20 carbon atoms; R is lower alkyl, lower alkenyl,lower alkynyl, phenyl, naphthyl, phenylalkyl or naphthylalkyl; x is aninteger from 1 to about 3, provided that when X is greater than 1,different occurrences of the --COOR group may be the same or different;Ar is phenyl or naphthyl optionally substituted with acetamido, amino,nitro, lower alkylamino, hydroxy, lower hydroxyalkyl, acetyl or cyanowith the proviso that when Ar is unsubstituted phenyl or naphthyl, Rcannot be lower alkyl, lower alkenyl or lower alkynyl, or apharmaceutically acceptable salt thereof.
 2. The method of claim 1wherein R is lower alkyl of from 1 to about 10 carbon atoms, loweralkenyl of from 3 to about 10 carbon atoms or lower alkynyl of from 2 toabout 10 carbon atoms.
 3. The method of claim 1, wherein Y is a straightor branched carbon chain of from 1 to about 6 carbon atoms or aralkyl offrom 8 to about 12 carbon atoms.
 4. The method of claim 1 wherein Ar issubstituted with acetamido, amino, nitro, lower alkylamino of from 1 toabout 5 carbon atoms, hydroxy, lower hydroxyalkyl of from 1 to about 5carbon atoms, acetyl, or cyano.
 5. The method of claim 4 wherein Y is astraight or branched carbon chain of from 1 to about 4 carbon atoms andx is 1 or
 2. 6. The method of claim 1 wherein Ar is unsubstituted phenylor phenyl substituted with acetamido, amino, nitro, hydroxy or cyano,and x is
 1. 7. The method of claim 6 wherein Ar is phenyl and x is
 1. 8.The method of claim 1 wherein the topically applied compound is ahydrochloride, sulfate, phosphate, gluconate or tartrate acid additionsalt.
 9. The method of claim 1 wherein the compound is administered as asolution of about 0.01% to about 10% by weight of the active ingredientin an opthalmologically acceptable carrier.
 10. The method of claim 9wherein the compound is administered as a solution of about 0.5% toabout 5% by weight of the active ingredients in an opthalmologicallyacceptable carrier.
 11. The method of claim 1 wherein the unit dosage ofthe active compound ranges from about 0.001 mg to about 5.0 mg.
 12. Themethod of claim 11 wherein the unit dosage of the active compound rangesfrom about 0.05 mg to about 2.0 mg.
 13. The method of claim 1 whereinthe active compound is contained in a sterile, aqueous, buffered,isotonic solution.
 14. A method for treating glaucoma or for loweringintraocular pressure in a mammal, which comprises topically applying tothe eye of such mammal an intraocular pressure-lowering effective amountof a compound represented by the formula: ##STR11## wherein Y is astraight or branched carbon chain of from 1 to about 10 carbon atoms oraralkyl of from 8 to about 20 carbon atoms; R is lower alkyl, loweralkenyl, lower alkynyl or phenyl; x is an integer from 1 to about 3,provided that when x is greater than 1, different occurrences of the--COOR group may be the same of different; Ar is phenyl optionallysubstituted with acetamido, amino, nitro, lower alkylamino, hydroxy,lower hydroxyalkyl, acetyl or cyano, with the proviso that when Ar isunsubstituted phenyl, R cannot be lower alkyl, lower alkenyl or loweralkynyl, or a pharmaceutically acceptable salt thereof.
 15. The methodof claim 14 wherein Ar is phenyl or phenyl substituted with acetamido,amino, hydroxy or cyano.
 16. The method of claim 15 wherein thetopically applied compound is a hydrochloride, sulfate, phosphate,gluconate or tartrate acid addition salt.
 17. The method of claim 14wherein the compound is administered as a solution of about 0.01% toabout 10% by weight of the active ingredient in an opthalmologicallyacceptable carrier.
 18. The method of claim 17 wherein the compound isadministered as a solution of about 0.5% to about 5% by weight of theactive ingredients in an opthalmologically acceptable carrier.
 19. Themethod of claim 14 wherein the unit dosage of the active compound rangesfrom about 0.001 mg to about 5.0 mg.
 20. The method of claim 19 whereinthe unit dosage of the active compound ranges from about 0.05 mg toabout 2.0 mg.
 21. The method of claim 15 wherein the active compound iscontained in a sterile, aqueous, buffered, isotonic solution.